Pharmaceutically useful salts of carboxylic acid derivates

ABSTRACT

A calcium or a magnesium salt of (2S)-2-ethoxy-3-(4-{2[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoic acid.

FIELD OF THE INVENTION

The present invention relates to certain novel salts of(2S)-3-(4-{2-[amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acidderivatives, to processes for preparing such compounds, to their theutility in treating clinical conditions including lipid disorders(dyslipidemias) whether or not associated with insulin resistance andother manifestations of the metabolic syndrome, to methods for theirtherapeutic use and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The metabolic syndrome including type 2 diabetes mellitus, refers to acluster of manifestations including insulin resistance with accompanyinghyperinsulinaemia, possibly type 2 diabetes mellitus, arterialhypertension, central (visceral) obesity, dyslipidaemia observed asderanged lipoprotein levels typically characterised by elevated VLDL(very low density lipoproteins), small dense LDL particles and reducedHDL (high density lipoprotein) concentrations and reduced fibrinolysis.

Recent epidemiological research has documented that individuals withinsulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In type 2 diabetes mellitus atherosclerosis relatedconditions cause up to 80% of all deaths.

In clinical medicine there is awareness of the need to increase theinsulin sensitivity in patients with the metabolic syndrome and thus tocorrect the dyslipidaemia which is considered to cause the acceleratedprogress of atherosclerosis. However, currently this is not auniversally accepted diagnosis with well-defined pharmacotherapeuticindications.

Co-pending PCT application No. PCT/GB02/05743 discloses compounds offormula A

wherein n is 1 or 2 and pharmaceutically acceptable salts, solvates,crystalline forms and prodrugs thereof are highly potent PPARαmodulators. PPAR is short peroxisome proliferator-activated receptors(for for a review of the PPARs see T. M. Willson et al, J Med Chem 2000,Vol 43, 527). These compounds are effective in treating conditionsassociated with insulin resistance. Specific pharmaceutically acceptablesalts of compounds of the formula A are not disclosed in PCT/GB02/05743.Further, no information is provided in relation to how crystalline formsof compounds of the formula A, and particularly salts thereof, may beprepared. The compound in which n is 2 is prepared as the free acid inthis application. However, this compound is a syrup and is not suitablefor use in pharmaceutical formulations. Therefore there exists a needfor a derivative of this compound which has physical and chemicalproperties suitable for use in pharmaceutical formulations. Attemptswere made to produce salts with many different counter-ions. However,most were unsatisfactory for one of the following reasons. A salt couldnot be formed in the solid state or if formed the salt was amorphouswith a low glass transition temperature.

In the formulation of drug compositions, it is important for the drugsubstance to be in a form in which it can be conveniently handled andprocessed. This is of importance, not only from the point of view ofobtaining a commercially-viable manufacturing process, but also from thepoint of view of subsequent manufacture of pharmaceutical formulationscomprising the active compound.

Further, in the manufacture of drug compositions, it is important that areliable, reproducible and constant plasma concentration profile of drugis provided following administration to a patient.

Chemical stability, solid state stability, and “shelf life” of theactive ingredients are also very important factors. The drug substance,and compositions containing it, should preferably be capable of beingeffectively stored over appreciable periods of time, without exhibitinga significant change in the active component's physico-chemicalcharacteristics (e.g. its chemical composition, density, hygroscopicityand solubility).

Moreover, it is also important to be able to provide drug in a formwhich is as chemically pure as possible.

The skilled person will appreciate that, typically, if a drug can bereadily obtained in a stable form, such as a stable crystalline form,advantages may be provided, in terms of ease of handling, ease ofpreparation of suitable pharmaceutical formulations, and a more reliablesolubility profile.

DESCRIPTION OF THE INVENTION

The present invention provides a calcium or a magnesium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid.

We have found that certain compounds of the invention have the advantagethat they may be prepared in crystalline form.

According to a further aspect of the invention there is provided acompound of the invention in substantially crystalline form.

Although we have found that it is possible to produce compounds of theinvention in forms which are greater than 80% crystalline, by“substantially crystalline” we include greater than 20%, preferablygreater than 30%, and more preferably greater than 40% (e.g. greaterthan any of 50, 60, 70, 80 or 90%) crystalline.

According to a further aspect of the invention there is also provided acompound of the invention in partially crystalline form. By “partiallycrystalline” we include 5% or between 5% and 20% crystalline.

The degree (%) of crystallinity may be determined by the skilled personusing X-ray powder diffraction (XRPD). Other techniques, such as solidstate NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry(DSC) and microcalorimetry, may also be used.

Compounds of the invention, and particularly crystalline compounds ofthe invention, may have improved stability when compared to compoundsdisclosed in PCT/GB02/05743.

The term “stability” as defined herein includes chemical stability andsolid state stability.

By “chemical stability”, we include that it may be possible to storecompounds of the invention in an isolated form, or in the form of aformulation in which it is provided in admixture with pharmaceuticallyacceptable carriers, diluents or adjuvants (e.g. in an oral dosage form,such as a tablet, capsule etc.), under normal storage conditions, withan insignificant degree of chemical degradation or decomposition.

By “solid state stability”, we include that it may be possible to storecompounds of the invention in an isolated solid form, or in the form ofa solid formulation in which it is provided in admixture withpharmaceutically acceptable carriers, diluents or adjuvants (e.g. in anoral dosage form, such as a tablet, capsule etc.), under normal storageconditions, with an insignificant degree of solid state transformation(e.g. crystallisation, recrystallisation, solid state phase transition,hydration, dehydration, solvatisation or desolvatisation).

Examples of “normal storage conditions” include temperatures of betweenminus 80 and plus 50° C. (preferably between 0 and 40° C. and morepreferably room temperatures, such as 15 to 30° C.), pressures ofbetween 0.1 and 2 bars (preferably at atmospheric pressure), relativehumidities of between 5 and 95% (preferably 10 to 60%), and/or exposureto 460 lux of UV/visible light, for prolonged periods (i.e. greater thanor equal to six months). Under such conditions, compounds of theinvention may be found to be less than 15%, more preferably less than10%, and especially less than 5%, chemically degraded/decomposed, orsolid state transformed, as appropriate. The skilled person willappreciate that the above-mentioned upper and lower limits fortemperature, pressure and relative humidity represent extremes of normalstorage conditions, and that certain combinations of these extremes willnot be experienced during normal storage (e.g. a temperature of 50° C.and a pressure of 0.1 bar).

It may be possible to crystallise salts of compounds of the presentinvention with or without the presence of a solvent system (e.g.crystallisation may be from a melt, under supercritical conditions, orachieved by sublimation). However, we prefer that crystallisation occursfrom an appropriate solvent system.

According to a further aspect of the invention, there is provided aprocess for the preparation of a crystalline compound of the inventionwhich comprises crystallising a compound of the invention from anappropriate solvent system.

Crystallisation temperatures and crystallisation times depend upon thesalt that is to be crystallised, the concentration of that salt insolution, and the solvent system which is used.

Crystallisation may also be initiated and/or effected by way of standardtechniques, for example with or without seeding with crystals of theappropriate crystalline compound of the invention.

Different crystalline forms of the compounds of the invention may bereadily characterised using X-ray powder diffraction (XRPD) methods, forexample as described hereinafter.

In order to ensure that a particular crystalline form is prepared in theabsence of other crystalline forms, crystallisations are preferablycarried out by seeding with nuclei and/or seed crystals of the desiredcrystalline form in substantially complete absence of nuclei and/or seedcrystals of other crystalline forms. Seed crystals of appropriatecompound may be prepared, for example, by way of slow evaporation ofsolvent from a portion of solution of appropriate salt.

Compounds of the invention may be isolated using techniques which arewell known to those skilled in the art, for example decanting, filteringor centrifuging.

Compounds may be dried using standard techniques.

Further purification of compounds of the invention may be effected usingtechniques, which are well known to those skilled in the art. Forexample impurities may be removed by way of recrystallisation from anappropriate solvent system. Suitable temperatures and times for therecrystallisation depend upon the concentration of the salt in solution,and upon the solvent system which is used.

When compounds of the invention are crystallised, or recrystallised, asdescribed herein, the resultant salt may be in a form which has improvedchemical and/or solid state stability, as mentioned hereinbefore.

Compounds of the invention have the advantage that they may be moreefficacious, be less toxic, be longer acting, have a broader range ofactivity, be more potent, produce fewer side is effects, be more easilyabsorbed, and/or have a better pharmacokinetic profile (e.g. higher oralbioavailability and/or lower clearance), than, and/or have other usefulpharmacological, physical, or chemical, properties over, compounds knownin the prior art. Compounds of the invention may have the furtheradvantage that they may be administered less frequently than compoundsknown in the prior art.

Compounds of the invention may also have the advantage that they are ina form which provides for improved ease of handling. Further, compoundsof the invention have the advantage that they may be produced in formswhich may have improved chemical and/or solid state stability (includinge.g. due to lower hygroscopicity). Thus, such compounds of the inventionmay be stable when stored over prolonged periods.

In another aspect the invention provides the salts of the presentinvention wherein a suitable stoichiometric ratio of base to free acidin the range 0.25:1.5 to 3.0:1, such as 0.45:1.25 to 1.25:1, including0.50:1 to 1:1.

Compounds of the invention may also have the advantage that they may becrystallised in good yields, in a high purity, rapidly, conveniently,and at a low cost.

The compounds of the present invention have activity as medicaments. Inparticular the compounds are highly potent agonists of PPARα. Inaddition the compounds of the present invention are also agonists ofPPAR_(γ). The term agonists as used herein, includes partial agonists.

The compounds of the invention may also be in the form of a mixed saltsuch as e.g. calcium chloride(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoatedihydrate. It will also be understood that certain crystalline compoundsof the present invention may exist in solvated, for example hydrated, aswell as unsolvated and unsolvated forms. It is to be understood that thepresent invention encompasses all such solvated forms.

Specific compounds of the invention are:

-   (2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoic    acid magnesium salt; and-   calcium chloride    (2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate    dihydrate.

The present invention also provides the following embodiments.

A calcium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid, characterised by an X-ray powder diffraction pattern characterisedby peaks with d-values at 31.1, 10.5, 7.7 and 4.63 Å.

A calcium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid having the XRPD pattern substantially as disclosed in figure A.

A magnesium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid characterised by an X-ray powder diffraction pattern characterisedby peaks with d-values at 30.5 and 10.2 Å.

A magnesium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid A having the XRPD pattern substantially as disclosed in figure B.

Methods of Preparation

The compounds of the present invention may be prepared by reacting(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid with sodium hydroxide in an inert solvent at a temperature in therange of 0-100° C. and then adding water followed by a water solublecalcium or magnesium salt, for example calcium chloride or magnesiumchloride or magnesium acetate and isolating the solid salt. The salt maybe isolated by cooling the reaction solution and optionally seeding thesolution with the desired product and/or concentrating the solution.Optionally the product may be isolated by adding an antisolvent to asolution of the product in an inert solvent. Suitable solvents includeisopropanol, ethanol or isopropyl acetate. Suitable antisolvents includeisooctane and diisopropyl ether. The solid may be collected by methodsknown to those skilled in the art for example filtration orcentrifugation.

In another aspect the present invention provides the compound obtainableby reacting(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid with sodium hydroxide to form a solution in an inert solvent,adding calcium chloride and then isolatimg the product.

Pharmaceutical Preparations

The compounds of the invention will normally be administered via theoral, parenteral, intravenous, intramuscular, subcutaneous or in otherinjectable ways, buccal, rectal, vaginal, transdermal and/or nasal routeand/or via inhalation, in the form of pharmaceutical preparations in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated and the route of administration, the compositionsmay be administered at varying doses.

Suitable daily doses of the compound of the invention in therapeuticaltreatment of humans are about 0.0001-100 mg/kg body weight, preferably0.001-10 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules whichmay be formulated by methods known to those skilled in the art toprovide doses of the active compound in the range of 0.5 mg to 500 mgfor example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including the compound of the invention inadmixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

Pharmacological Properties

The compounds of the invention is useful for the prophylaxis and/ortreatment of clinical conditions associated with inherent or inducedreduced sensitivity to insulin (insulin resistance) and associatedmetabolic disorders (also known as metabolic syndrome). These clinicalconditions will include, but will not be limited to, general obesity,abdominal obesity, arterial hypertension, hyperinsulinaemia,hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristicallyappearing with insulin resistance. This dyslipidaemia, also known as theatherogenic lipoprotein profile, is characterised by moderately elevatednon-esterified fatty acids, elevated very low density lipoprotein (VLDL)triglyceride rich particles, high Apo B levels, low high densitylipoprotein (HDL) levels associated with low apoAI particle levels andhigh Apo B levels in the presence of small, dense, low densitylipoproteins (LDL) particles, phenotype B.

The compounds of the present invention are expected to be useful intreating patients with combined or mixed hyperlipidemias or variousdegrees of hypertriglyceridemias and postprandial dyslipidemia with orwithout other manifestations of the metabolic syndrome.

Treatment with the present compounds is expected to lower thecardiovascular morbidity and mortality associated with atherosclerosisdue to their antidyslipidaemic as well as antiinflammatory properties.The cardiovascular disease conditions include macro-angiopathies ofvarious internal organs causing myocardial infarction, congestive heartfailure, cerebrovascular disease and peripheral arterial insufficiencyof the lower extremities. Because of its insulin sensitizing effect thecompound is also expected to prevent or delay the development of type 2diabetes from the metabolic syndrome and diabetes of pregnancy.Therefore the development of long-term complications associated withchronic hyperglycaemia in diabetes mellitus such as themicro-angiopathies causing renal disease, retinal damage and peripheralvascular disease of the lower limbs are expected to be delayed.Furthermore the compound may be useful in treatment of variousconditions outside the cardiovascular system whether or not associatedwith insulin resistance, like polycystic ovarian syndrome, obesity,cancer and states of inflammatory disease including neurodegenerativedisorders such as mild cognitive impairment, Alzheimer's disease,Parkinson's disease and multiple sclerosis.

The compounds of the present invention are expected to be useful incontrolling glucose levels in patients suffering from type 2 diabetes.

The present invention provides a method of treating or preventingdyslipidemias, the insulin resistance syndrome and/or metabolicdisorders (as defined above) comprising the administration of a compoundof the present invention to a mammal (particularly a human) in needthereof.

The present invention provides a method of treating or preventing type 2diabetes comprising the administration of an effective amount of acompound of the present invention to a mammal (particularly a human) inneed thereof.

In a further aspect the present invention provides the use of a compoundof the present invention as a medicament.

In a further aspect the present invention provides the use of a compoundof the present invention in the manufacture of a medicament for thetreatment of insulin resistance and/or metabolic disorders.

Combination Therapy

The compounds of the invention may be combined with another therapeuticagent that is useful in the treatment of disorders associated with thedevelopment and progress of atherosclerosis such as hypertension,hyperlipidaemias, dyslipidaemias, diabetes and obesity. The compound ofthe invention may be combined with another therapeutic agent thatdecreases the ratio of LDL:HDL or an agent that causes a decrease incirculating levels of LDL-cholesterol. In patients with diabetesmellitus the compound of the invention may also be combined withtherapeutic agents used to treat complications related tomicro-angiopathies.

A compound of the invention may be used alongside other therapies forthe treatment of metabolic syndrome or type 2 diabetes and itsassociated complications, these include biguanide drugs, for examplemetformin, phenformin and buformin, insulin (synthetic insulinanalogues, amylin) and oral antihyperglycemics (these are divided intoprandial glucose regulators and alpha-glucosidase inhibitors). Anexample of an alpha-glucosidase inhibitor is acarbose or voglibose ormiglitol. An example of a prandial glucose regulator is repaglinide ornateglinide.

In another aspect of the invention, the compound of formula I, or apharmaceutically acceptable salt thereof, may be administered inassociation with a PPAR modulating agent. PPAR modulating agents includebut are not limited to a PPAR alpha and/or gamma and/or delta agonist,or pharmaceutically acceptable salts, solvates, solvates of such saltsor prodrugs thereof. Suitable PPAR alpha and/or gamma agonists,pharmaceutically acceptable salts, solvates, solvates of such salts orprodrugs thereof are well known in the art. These include the compoundsdescribed in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO99/62871, WO 98/57941, WO 01/40170, WO 04/000790, WO 04/000295, WO04/000294, WO 03/051822, WO 03/051821, WO 02/096863, WO 03/051826, WO02/085844, WO 01/040172, J Med Chem, 1996, 39, 665, Expert Opinion onTherapeutic Patents, 10 (5), 623-634 (in particular the compoundsdescribed in the patent applications listed on page 634) and J Med Chem,2000, 43, 527 which are all incorporated herein by reference.Particularly a PPAR alpha and/or gamma and/or delta agonist refers tomuraglitazar (BMS 298585), rivoglitazone (CS-011), netoglitazone(MCC-555), balaglitazone (DRF-2593, NN-2344), clofibrate, fenofibrate,bezafibrate, gemfibrozil, ciprofibrate, pioglitazone, rosiglitazone,AVE-0847, AVE-8134, CLX-0921, DRF-10945, DRF-4832, LY-518674, LY-818,LY-929, 641597, GW-590735, GW-677954, GW-501516, MBX-102, ONO-5129,KRP-101, R-483 (BM131258), TAK-559 or TAK-654. Particularly a PPAR alphaand/or gamma and/or delta agonist refers to tesaglitazar((S)-2-ethoxy-3-[4-(2-{4-methanesulphonyl-oxyphenyl}ethoxy)phenyl]propanoicacid) and pharmaceutically acceptable salts thereof.

In addition a compound of the invention may be used in conjunction witha sulfonylurea for example: glimepiride, glibenclamide (glyburide),gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide,acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid,glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide,phenbutamide, tolcylamide and tolazamide. Preferably the sulfonylurea isglimepiride or glibenclamide (glyburide). More preferably thesulfonylurea is glimepiride. The present invention includesadministration of a compound of the present invention in conjunctionwith one, two or more existing therapies described in this combinationsection. The doses of the other existing therapies for the treatment oftype 2 diabetes and its associated complications will be those known inthe art and approved for use by regulatory bodies for example the FDAand may be found in the Orange Book published by the FDA. Alternativelysmaller doses may be used as a result of the benefits derived from thecombination. The present invention also includes a compound of thepresent invention in combination with a cholesterol-lowering agent. Thecholesterol-lowering agents referred to in this application include butare not limited to inhibitors of HMG-CoA reductase(3-hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoAreductase inhibitor is a statin selected from the group consisting ofatorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin,itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatinand simvastatin, or a pharmaceutically acceptable salt, especiallysodium or calcium, or a solvate thereof, or a solvate of such a salt. Aparticular statin is atorvastatin, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. A moreparticular statin is atorvastatin calcium salt. A particularly preferredstatin is, however, a compound with the chemical name(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, [also known as(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] or a pharmaceutically acceptable salt or solvate thereof, or asolvate of such a salt. The compound(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, and its calcium and sodium salts are disclosed in European PatentApplication, Publication No. EP-A-0521471, and in Bioorganic andMedicinal Chemistry, (1997), 5(2), 437-444. This latter statin is nowknown under its generic name rosuvastatin.

In the present application, the term “cholesterol-lowering agent” alsoincludes chemical modifications of the HMG-CoA reductase inhibitors,such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present inventionin combination with a bile acid sequestering agent, for examplecolestipol or cholestyramine or cholestagel.

The present invention also includes a compound of the present inventionin combination with an inhibitor of the ileal bile acid transport system(IBAT inhibitor).

Suitable compounds possessing IBAT inhibitory activity have beendescribed, see for instance the compounds described in WO 93/16055, WO94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/50051, EP 864582, EP489423, EP549967, EP573848, EP624593, EP624594, EP624595 andEP624596 and the contents of these patent applications are incorporatedherein by reference. Further suitable compunds possessing IBATinhibitory activity have been described in WO 94/24087, WO 98/56757, WO00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO 01/34570, WO00/35889, WO 01/68637, WO 02/08211, WO 03/020710, WO 03/022825, WO03/022830, WO 03/022286, WO 03/091232, WO 03/106482, JP 10072371, U.S.Pat. No. 5,070,103, EP 251 315, EP 417 725, EP 869 121, EP 1 070 703 andEP 597.107 and the contents of these patent applications areincorporated herein by reference.

Particular classes of IBAT inhibitors suitable for use in the presentinvention are benzothiepines, and the compounds described in the claims,particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 areincorporated herein by reference. Other suitable classes of IBATinhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and1,5-benzothiazepines. A further suitable class of IBAT inhibitors is the1,2,5-benzothiadiazepines.

One particular suitable compound possessing IBAT inhibitory activity is(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl□-D-glucopyranosiduronic acid (EP 864 582). Other suitable IBATinhibitors include one, of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)    phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(hydroxy)    phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    and-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the present invention the formula Aoptionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

a CETP (cholesteryl ester transfer protein) inhibitor, for example thosereferenced and described in WO 00/38725 page 7 line 22-page 10, line 17which are incorporated herein by reference;

a cholesterol absorption antagonist for example azetidinones such as SCH58235 and those described in U.S. Pat. No. 5,767,115 which areincorporated herein by reference;

a MTP (microsomal transfer protein) inhibitor for example thosedescribed in Science, 282, 751-54, 1998 which are incorporated herein byreference;

a nicotinic acid derivative, including slow release and combinationproducts, for example, nicotinic acid (niacin), acipimox and niceritrol;

a phytosterol compound for example stanols;

probucol;

an omega-3 fatty acid for example Omacor™;

an anti-obesity compound for example orlistat (EP 129,748) andsibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);

an antihypertensive compound for example an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin II receptor antagonist, anandrenergic blocker, an alpha andrenergic blocker, a beta andrenergicblocker for example metoprolol, a mixed alpha/beta andrenergic blocker,an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, asaluretic, a diuretic or a vasodilator;

a CB1 antagonist or inverse agonist for example as described inWO01/70700 and EP 65635;

aspirin;

a Melanin concentrating hormone (MCH) antagonist;

a PDK inhibitor; or

modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of theinvention include but are not limited to, the following compounds:alacepril, alatriopril, altiopril calcium, ancovenin, benazepril,benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of the invention include, but are notlimited to, compounds: candesartan, candesartan cilexetil, losartan,valsartan, irbesartan, tasosartan, telmisartan and eprosartan.Particularly preferred angiotensin II antagonists or pharmaceuticallyacceptable derivatives thereof for use in the present invention arecandesartan and candesartan cilexetil.

Therefore in an additional feature of the invention, there is provided amethod for for the treatment of type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of the present invention in simultaneous,sequential or separate administration with an effective amount of onethe other compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of the present inventionof a compound of the invention in simultaneous, sequential or separateadministration with an effective amount of one the other compoundsdescribed in this combination section or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the presentinvention and one of the other compounds described in this combinationsection or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof, in association with a pharmaceuticallyacceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of the present invention and one of theother compounds described in this combination section or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of the present invention in a first unit dosage form;

b) one of the other compounds described in this combination section or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof; in a second unit dosage form; and

c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of the present invention together with a pharmaceuticallyacceptable diluent or carrier, in a first unit dosage form;

b) one of the other compounds described in this combination section or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in a second unit dosage form; and

c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the present invention of the present invention and oneof the other compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in the manufacture of a medicament for use in the thetreatment of metabolic syndrome or type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the present invention and one of the other compoundsdescribed in this combination section, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in themanufacture of a medicament for use in the treatment of hyperlipidaemicconditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the present invention optionally together with apharmaceutically acceptable diluent or carrier, with the simultaneous,sequential or separate administration of an effective amount of one ofthe other is compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

The expression “inert solvent” refers to a solvent that does not reactwith the starting materials, reagents, intermediates or products in amanner which adversely affects the yield of the desired product.

EXPERIMENTAL

¹H NMR and ¹³C NMR measurements were performed on a Varian Mercury 300or Varian UNITY plus 400, 500 or 600 spectrometers, operating at ¹Hfrequencies of 300, 400, 500 and 600 MHz, respectively, and at ¹³Cfrequencies of 75, 100, 125 and 150 MHz, respectively. Measurements weremade on the delta scale (δ).

Unless otherwise stated, chemical shifts are given in ppm with thesolvent as internal standard.

X-ray powder diffraction analysis (XRPD) was performed using variableslits on samples prepared according to standard methods with and/orwithout using any internal standard. Standard methods are described in,for example, Giacovazzo, C. et al (1995), Fundamentals ofCrystallography, Oxford University Press; Jenkins, R. and Snyder, R. L.(1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons,New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press,London; or Klug, H. P. & Alexander, L. E. (1974), X-ray DiffractionProcedures, John Wiley and Sons, New York. X-ray analyses were performedusing Cu-radiation a Siemens D5000 diffractometer or a Philips X'PertMPD. The X-axis in the figures below is 2-theta and the Y axis isintensity.

Differential scanning calorimetry (DSC) was performed using a MettlerDSC820, a Mettler DSC820E or a Perkin Elmer DSC 7 instrument, accordingto standard methods, for example those described in Höhne, G. W. H. etal (1996), Differential Scanning Calorimetry, Springer, Berlin.

Thermo-gravimetric analysis (TGA) was performed using a Mettler ToledoTGA850, a Mettler Toledo TG851 or a Perkin Elmer TGA 7 instrument.

It will be appreciated by the skilled person that crystalline forms ofcompounds of the invention may be prepared by analogy with processesdescribed herein and/or in accordance with the Examples below, and mayshow essentially the same XRPD diffraction patterns and/or DSC and/orTGA thermograms as those disclosed herein. By “essentially the same”XRPD diffraction patterns and/or DSC and/or TGA thermograms, we includethose instances when it is clear from the relevant patterns and/orthermograms (allowing for experimental error) that essentially the samecrystalline form has been formed. When provided, DSC onset temperaturesmay vary in the range ±5° C. (e.g. ±2° C.), and XRPD distance values mayvary in the range ±2 on the last decimal place. It will be appreciatedby the skilled person that XRPD intensities may vary when measured foressentially the same crystalline form for a variety of reasonsincluding, for example, preferred orientation.

Abbreviations

DMSO dimethyl sulfoxide

THF tetrahydrofuran

Pd/C palladium on charcoal

DMAP dimethylaminopyridine

t triplet

s singlet

d doublet

q quartet

m multiplet

bs broad singlet

dm doublet of multiplet

bt broad triplet

dd doublet of doublet

XRPD X-ray powder diffraction

TGA thermogravimetric analysis

DSC differential scanning calorimetry

EXAMPLES

Preparation of Starting Material

Method 1

(2S)-2-Ethoxy-3-(4-[2-hexyl(2-phenylethyl)amino-2-oxoethoxy]phenyl)propanoicacid (i) Ethyl(2S)-3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-2-ethoxypropanoate

To a solution of ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (23.8g, 100 mmol, prepared as described in WO99/62872) in acetonitrile (200mL) was added anhydrous potassium carbonate (31.9 g, 231 mmol) followedby benzyl bromoacetate (17.4 mL, 110 mmol) and the reaction mixture wasrefluxed overnight. The reaction mixture was allowed to cool to roomtemperature, insoluble salts were filtered off and the solution wasconcentrated in vacuo. The residue was taken up in ethyl acetate (300mL), and the organic phase was washed with aqueous NaHCO₃ (3×100 mL) andbrine (100 mL), dried over anhydrous MgSO₄, and concentrated in vacuo.Purification on silica gel with methylene chloride as the eluent andcollection of pure fractions yielded 22.4 g (58%) of a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H), 1.22 (t, 3H), 2.93-2.97 (m,2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.97 (m, 1H), 4.16 (q, 2H), 4.64 (s,2H), 5.23 (s, 2H), 6.82 (d, 2H), 7.15 (d, 2H), 7.32-7.39 (m, 5H).

¹³C NMR (100 MHz, CDCl₃): δ 14.3, 15.2, 38.6, 60.9, 65.6, 66.3, 67.0,80.4, 114.6, 128.5, 128.6, 128.7, 130.6, 135.3, 156.7, 169.0, 172.6.

(ii) {4-[(2S)-2,3-Diethoxy-3-oxopropyl]phenoxy}acetic acid

To a solution of ethyl(2S)-3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-2-ethoxypropanoate (22.33g, 57.8 mmol) in freshly distilled THF (290 mL) was added Pd/C (10%, 3.1g) and the reaction mixture was hydrogenated under atmospheric pressureat room temperature overnight. The mixture was filtered through a plugof Celite and the filtrate was concentrated in vacuo to afford 16.6 g(97%) of a light yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 1.15 (t, 3H), 1.21 (t, 3H), 2.93-2.98 (m,2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.97 (m, 1H), 4.16 (q, 2H), 4.65 (s,2H), 6.84 (d, 2H), 7.17 (d, 2H), 8.48 (bs, 1H)

¹³C NMR (100 MHz, CDCl₃): δ 14.3, 15.1, 38.5, 61.0, 65.1, 66.4, 80.3,114.6, 130.7, 130.9, 156.4, 172.7, 173.7

(iii) Ethyl(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate

To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid(0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were addedhexyl(2-phenylethyl)amine (0.080 g, 0.39 mmol) and DMAP (0.045 g, 0.37mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.071 g, 0.37 mmol), and the reaction mixture was stirredat room temperature overnight. The mixture was diluted with methylenechloride (25 mL), and the organic phase was washed with 5% HCl (3×25mL), aqueous NaHCO₃ (25 mL) and brine (25 mL), dried over Na₂SO₄ andconcentrated in vacuo. Purification on a prepacked column of silica gel(Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) inmethylene chloride as the eluent yielded 0.125 g (70%) of a colourlessoil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.92 (m, 3H), 1.16 (t, 3H), 1.19-1.33(m, 9H), 1.45-1.65 (m, 2H), 2.82-2.90 (m, 2H), 2.91-2.98 (m, 2H),3.12-3.21 and 3.29-3.42 (2m, 3H, rotamers) 3.50-3.65 (m, 3H), 3.95 (m,1H), 4.16 (q, 2H), 4.39 and 4.65 (2s, 2H, rotamers), 6.75 and 6.86 (2d,2H, rotamers), 7.10-7.34 (m, 7H).

¹³C NMR (100 MHz, CDCl₃): δ14.0, 14.1, 14.3, 15.1, 22.6, 26.5, 26.7,27.4, 29.0, 31.5, 31.6, 33.9, 35.3, 38.5, 45.9, 48.1, 48.3, 48.9, 60.8,66.2, 67.5, 80.4, 114.5, 126.4, 126.9, 128.5, 128.9, 130.1, 130.2,130.5, 130.5, 138.3, 139.2, 156.9, 157.0, 167.6, 167.8, 172.5. (Thenumber of peaks is larger than the number of carbon atoms due torotamers.)

(iv)(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid

To a solution of ethyl(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate(0.081 g, 0.17 mmol) in THF (8.6 mL) was added 4.3 mL of a 0.10 M LiOHsolution and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was acidified with 2M HCl and extractedwith ethyl acetate (3×25 mL). The combined organic phase was washed withbrine (25 mL), dried over Na₂SO₄, and concentrated in vacuo to afford0.073 g (96%) of a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 0.82-0.93 (m, 3H), 1.15 (t, 3H), 1.20-1.35(m, 6H), 1.47-1.62 (m, 2H), 2.80-2.99 (m, 3H), 3.00-3.09 (m, 1H),3.11-3.21 and 3.31-3.44 (2m, 3H, rotamers), 3.50-3.67 (m, 3H), 4.01 (m,1H), 4.40 and 4.66 (2s, 2H, rotamers), 6.75 and 6.85 (2d, 2H, rotamers),7.10-7.35 (m, 7H), 8.86 (bs, 1H).

¹³C NMR (100 MHz, CDCl₃): δ 14.0, 14.1, 15.1, 22.6, 22.6, 26.6, 26.7,27.3, 28.9, 31.5, 31.6, 33.8, 35.2, 38.1, 46.1, 48.3, 48.4, 49.0, 66.7,67.4, 79.9, 114.6, 126.4, 127.0, 128.6, 128.9, 130.0, 130.1, 130.6,130.7, 138.2, 139.1, 156.9, 157.0, 168.1, 168.2, 175.6. (The number ofpeaks is larger than the number of carbon atoms due to rotamers.)

Method 2

(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid

a) Phenethylamine (30.0 g) was treated with 6M aqueous sodium hydroxide(61.5 ml) in toluene (100 ml). A solution of chloroacetyl chloride (28.0g) in toluene (50 ml) was added under temperature control. Aftercomplete reaction, the reaction slurry was warmed until a completesolution was obtained, and the water-phase was removed. The organicphase was washed with aqueous hydrogen chloride and water. The resultingtoluene phase was reduced by evaporation and diisopropylether was addedto the toluene solution. The solution was cooled and1-chloro-N-phenethylacetamide (42.3 g) was collected by filtration,washed and dried. The product was analysed by LC (99.8 area %) and NMR.

¹H NMR δ_(H)(400 MHz, CDCl₃): 2.88 (t, 2H), 3.60 (dd, 2H), 4.05 (s, 2H),6.62 (bs, 1H), 7.19-7.58 (m, 5H).

b) A mixture of potassium carbonate (31.5 g),1-chloro-N-phenethylacetamide (15.0 g), ethyl(2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (18.1 g) (see WO 99/62871)and acetonitrile (150 ml) was stirred and brought to the boil underreflux. After complete reaction, the mixture was cooled and theinorganic salts were filtered off and washed with acetonitrile. Theremaining solution was reduced by distillation and the product wascrystallised from ethyl acetate and hexanes. Ethyl(2S)-2-ethoxy-3-(4-{2-oxo-2-[(2-phenylethyl)amino]ethoxy}phenyl)propanoate (24.5 g) was collected by filtration, washed and dried. Theproduct was analysed by LC (98.6 area %) and NMR.

¹H NMR δ_(H)(400 MHz, CDCl₃): 1.18 (t, 3H), 1.26 (t, 3H), 2.86 (t, 2H),2.96-3.01 (m, 2H), 3.37 (dq, 1H), 3.58-3.68 (m, 3H), 4.00 (dd, 1H), 4.20(q, 2H), 4.47 (s, 2H), 6.65 (bs, 1H), 6.79 (dm, 2H), 7.14-7.36 (m, 7H).

c) A solution of ethyl(2S)-2-ethoxy-3-(4-{2-oxo-2-[(2-phenylethyl)amino]ethoxy}-phenyl)propanoate(36.0 g) in THF (270 ml) was added to a solution of lithium hydroxide(6.51 g) dissolved in water (360 ml). The mixture was stirred at roomtemperature. After complete reaction, the mixture was evaporated underreduced pressure to remove THF. After evaporation, the reaction mixturewas cooled to room temperature and acidified with hydrochloric acid. Theacidified product was extracted with ethyl acetate. The ethyl acetatesolution was washed with water and evaporated to a reduced volume. Theproduct was crystallised from ethyl acetate and diisopropyl ether.(2S)-2-Ethoxy-3-(4-{2-oxo-2-[(2-phenylethyl)amino]ethoxy}phenyl)-propanoic acid (28.0 g) was filtered off and washedwith diisopropyl ether and dried under vacuum.

¹H NMR δ_(H)(400 MHz, CDCl₃): 1.20 (t, 3H), 2.85 (t, 2H), 3.00 (dd, 1H),3.10 (dd, 1H), 3.46 (dq, 1H), 3.5.6-3.71 (m, 3H), 4.07 (dd, 1H), 4.45(s, 2H), 6.68 (bs, 1H), 6.78 (dm, 2H), 7.10-7.38 (m, 7H).

d) Dimethylsulfoxide (DMSO) (2750 mL), potassium hydroxide powder (244g) and(2S)-2-ethoxy-3-(4-{2-oxo-2-[(2-phenylethyl)amino]ethoxy}phenyl)propanoicacid (250 g) were stirred at approximately 18° C. for ca 20 minutes.1-Bromohexane (344 g=292 mL) was added over 2.5 hours. The reactionmixture was stirred for approximately 10 minutes. Diisopropyl ether(1000 mL) was added followed by filtration, extraction and separation ofthe mixture. The DMSO layer was further extracted with diisopropyl ether(2×1000 mL). The DMSO layer was acidified with 4M HCl(aq) (950 mL).Diisopropyl ether (3000 mL) and water (2500 mL) were added followed byextraction. The layers were separated (pH˜2 of aq layer) and thediisopropyl ether layer was washed with water (2500 mL). The diisopropylether layer was concentrated in vacuo to a clear, very viscous oil.Yield 317 g, assay 88.1%, corrected yield 91.1%, LC-purity 97.2%, e.e.97.8%. LC-purity and kiral LC in accordance with reference sample.

¹H NMR δ_(H)(400 MHz, CDCl₃): 0.75-0.85 (m, 3H), 1.10 (t, 3H), 1.14-1.29(m, 6H), 1.40-1.55 (m, 2H), 2.76-2.93 (m, 3H), 2.97-3.06 (m, 1H),3.06-3.14 and 3.28-3.43 (2m, 3H, rotamers), 3.45-3.58 (m, 3H), 3.98 (m,1H), 4.32 and 4.59 (2s, 2H, rotamers), 6.68 and 6.80 (2m, 2H, rotamers),7.02-7.31 (m, 8H).

Calcium Salts of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid Example 1

(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid (0.52 g) was dissolved in isopropanol (23 ml/g), NaOH (0.94 moleequiv) was added together with water (0.5 ml/g) followed by addition ofCaCl₂ (0.95 mole equiv). The solution was stirred at 40° C., and NaClwas formed. The NaCl was then filtered off and the excess of water inthe filtrate was evaporated off using the azeotrope between IPA andwater. The solution was concentrated to 5 ml/g and then antisolvent, amixture of isopropyl acetate and isooctane 50/50 (23 ml/g), was added.The product (0.48 g) was collected by filtration.

¹H-NMR (400 MHz, DMSO-d-6): 7.4-7.1 (6H, m), 7.05 (1H, d), 6.7 (1H, d),6.5 (1H, d), 4.7 (1H, s), 4.3 (1H, s), 3.65 (1H, m), 3.55-3.35 (3H, m),3.25 (1H, t), 3.15 (2H, m), 2.85 (2H, m), 2.75 (1H, t), 2.6 (1H, m),1.45 (2H, br s), 1.2 6H, br s), 0.95 (3H, m), 0.8 (3H, m).

Example 2

(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid (5.27 g) was dissolved in isopropyl acetate (10 ml/g), then NaOH(2.3 mole equiv) was added followed by addition of water (5 ml/g) andaddition of CaCl₂ (1 mole equiv). The solution was stirred in roomtemperature and the water phase was discarded. The organic phase wasevaporated with IPA (10 ml/g), then one more portion of CaCl₂ dissolvedin water (0.5 ml/g) was added at increased temperature (50° C.), andantisolvent, diisopropylether (10 ml/g) was added. The slurry was cooledto 0° C., and the product (3.48 g) was filtered off and identified ascalcium chloride(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino)]2-oxoethoxy}phenyl)propanoatedihydrate

¹H-NMR (400 MHz, DMSO-D6): 7.4-7.0 (7H, m), 6.7 (1H, d), 6.6 (1H, d),4.7 (1H, s), 4.5 (1H, s), 3.7 (1H, m), 3.5 (2H, m), 3.3 (2H, t), 3.2(2H, m), 2.9 (2H, m), 2.7 (2H, m), 1.5 (2H, br m), 1.2 (6H, br s), 1.0(3H, t), 0.9 (3H, m)

Magnesium salts of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid Example 3

(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid was dissolved in 95% ethanol, followed by addition of Mg(OAc)₂.4H₂O(1 mole equiv). The solution was stirred at room temperature, followedby evaporation to dryness and addition of isooctane (10 ml/g). Theslurry was stirred at room temperature, the product was collected byfiltration to give a magnesium salt of(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoatewhich was analysed by XRPD.

Example 4

(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate(0.10 g) was dissolved in isopropanol (19 ml/g), NaOH (1 mole equiv) wasadded together with water (19 ml/g) followed by addition of MgCl₂ (1.1mole equiv). The solution was stirred at 40° C., overnight. The solutionwas then clearfiltered and the filtrate was evaporated to drynessfollowed by addition of hexane (11 ml/g) and IPA (2 ml/g), and theslurry was stirred at ambient temperature. Magnesium(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate(0.099 g) was collected by filtration.

¹H-NMR (400 MHz, CD₃CN): 7.4-7.1 (7H, m), 6.8 (1H, d), 6.6 (1H, d), 4.7(1H, s), 4.4 (1H, s), 3.8 (1H, m), 3.5 (3H, m), 3.35 (1H, m), 3.2 (2H,m), 2.9 (2H, m), 2.7 (2H, m), 1.5 (2H, m), 1.3 (6H, br s), 1.0 (3H, t),0.85 (3H, br s).

Properties

1) Examples of properties of Calcium chloride salt of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid dihydrate

DSC showed an endotherm with an extrapolated onset temperature of 80° C.TGA showed a weight loss of 7.8% w/w between 24-150° C. DSC analysisrepeated on purer sample may give a higher melting point. Crystals ofthe Calcium chloride salt of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid (obtained by way of the example above and/or by other ways) wereanalyzed by XRPD and the results are tabulated below and are shown inFigure A

d-value intensity (Angstrom) (rel) 31.1 vs 15.6 m 10.5 vs 7.8 w 7.7 m7.3 w 7.2 w 5.2 w 5.1 w 4.9 w 4.8 w 4.63 m 4.56 w 4.19 w 4.12 m 3.92 w3.86 w 3.14 w

2) Examples of properties of Magnesium salt of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid

DSC showed an endotherm with an extrapolated onset temperature of 131°C. TGA showed a weight loss of 1.8% w/w between 24-70° C., 2.6% w/wbetween 70-110° C. and 3.3% w/w between 110-160° C. DSC analysisrepeated on purer sample may give a higher melting point. Crystals ofthe Magnesium salt of(2S)-2-Ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoicacid (obtained by way of the example above and/or by other ways) wereanalyzed by XRPD and the results are tabulated below and are shown inFigure B

d-value intensity (Angstrom) (rel) 30.5 vs 20.5 w 10.2 m 7.9 w 4.73 w4.30 w 4.00 wBiological Activity

Compound A was tested in the assays described in WO 03/051821.

The compounds of the present invention have an EC₅₀ of less than 0.5μmol/l for PPARα a

The compounds of the invention are more potent with respect to PPARαthan with respect to PPAR_(γ). It is believed that this relationship isimportant with respect to the pharmacological activity of the compoundsand to their therapeutic profile.

In addition the compounds of the present invention exhibit improved DMPK(Drug Metabolism and Pharmacokinetic) properties, for example theyexhibit improved metabolic stability in vitro, and also exhibitfavourable dose response curves in vivo. The compounds also have apromising toxicological profile.

1. A calcium or a magnesium salt of (2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)-amino]-2-oxoethoxy}phenyl)propanoic acid.
 2. A calcium salt of (2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoic acid.
 3. A salt as claimed in either claim 1 or claim 2 which is a solvate, a hydrate, a mixed solvate/hydrate, an ansolvate or an anhydrate.
 4. A salt as claimed in either claim 1 or claim 2 in crystalline or partially crystalline form.
 5. A salt as claimed in either claim 1 or claim 2 either in the form of a mixed salt together with a pharmaceutically inactive counterion.
 6. A salt as claimed in either claim 1 or claim 2 wherein the pharmaceutically inactive counterion is [CaCl]⁺.
 7. A pharmaceutical formulation comprising a compound according to either claim 1 or claim 2 in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
 8. A method of treating or preventing lipid disorders (dyslipidemia) whether or not associated with insulin resistance comprising the administration of a compound according to either claim 1 or claim 2 to a mammal in need thereof.
 9. (canceled)
 10. A method of treating or preventing type 2 diabetes comprising administering an effective amount of a compound of formula I according to either claim 1 or claim 2 to a mammal in need thereof.
 11. A pharmaceutical composition comprising a compound according to either claim 1 or claim 2 combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and obesity.
 12. A pharmaceutical formulation comprising a compound according to claim 5 with pharmaceutically acceptable adjuvants, diluents and/or carriers. 